(May 27, 1996) A dramatic change is afoot in the scientific
understanding of schizophrenia, a devastating mental illness with 2.5
million victims in the United States alone. The first symptoms usually
appear when people are in their late 20s, but neuroscientists now believe
that the seeds of the disorder are often sown during fetal development.

That is when the brain is wired up; nerve cells grow and divide, building
connections with each other. The basic flaw in the brains of many
schizophrenics seems to be that certain nerve cells migrate to the wrong
areas when the brain is first taking shape, leaving small regions of the
brain permanently out of place or miswired. Such errors in neural
architecture may have one or more causes, which remain to be discovered.
One speculation is that brain misconnections might develop when the mother
catches a virus early in pregnancy.[Note: newer research has identified stress during pregnancy, and lack of key nutrients during pregnancy - such as folic acid, choline, vitamin D and omega 3 fatty acids - are also likely contributors to brain development problems during pregnancy that predispose a child to schizophrenia].

The chief symptoms of schizophrenia include apathy, a blunting of
emotions, delusions and the hearing of internal voices. Once these
symptoms begin, they typically wax and wane for the rest of a person's
life.

The idea that these differences arise during fetal development, said Dr.
David Shore, chief of the Schizophrenia Research Branch at the National
Institute of Mental Health in Bethesda, Md., "is one of the leading
candidates for explaining how the changes we see in the brains of
schizophrenics might have come about."

But that theory does not solve the entire puzzle. "Schizophrenia
is
probably many different kinds of problems that converge on the same
syndrome, not just a single disease," said Dr. Daniel Weinberger,
chief of
the clinical Brain Disorders Branch of the National Institute of Mental
Health. "But based on the weight of evidence, half or more of
schizophrenia risk seems to be due to abnormalities in fetal brain
development."

Evidence for that new theory comes from several different sources,
including autopsies of patients' brains, family movies taken when patients
were as young as 2 and epidemiological data.

One of the more convincing reports, based on tissue from autopsies and
published this month in The Archives of General Psychiatry, showed neurons
out of place in the prefrontal areas of 7 of 20 brains from patients with
schizophrenia and in none of the 20 brains from people without the
disorder. The study is the fourth of its kind to report wayward cells
in
various parts of the cortex in people with schizophrenia.

The out-of-place cells are unexpectedly large residues of the neural
subplate, a structure that guides other neurons to their proper sites.
The
subplate forms about the fourth month of pregnancy. It gradually
disappears almost entirely within the first month of life, having
performed its task of aiming neurons toward their location in the cortex.

"The migration of brain cells through the neural subplate occurs
almost
entirely in the second trimester of fetal development," said Dr.
Steven G.
Potkin, a psychiatrist at the University of California at Irvine and a
co-author of the study, with Dr. William E. Bunney and Dr. Edward Jones.

"If you disrupt this migration, cells end up in the wrong place or
have
faulty connections -- and that's what we found in the brains of the
schizophrenic patients," Potkin said. "The maldistribution of
these cells
suggests an abnormality in the subplate."

Experiments on cats by Dr. Carla Shatz, a neuroscientist at the University
of California at Berkeley, has shown that making cuts in the subplate
at
an equivalent period in the development of the cat brain produces cortical
cells that are miswired or out of place.

Just what might cause the neural subplate to fail to perform its duties
is
a matter of surmise. Potkin speculated that "there may be a wide
range of
pregnancy-related causes, from a faulty genetic mechanism to environmental insults, like
the
mother having a virus that penetrates the placenta, nutritional deficiencies, stress
or other issues - all of which interfere with the operation of the neural subplate
during the critical months of fetal brain development."

One nagging question for proponents of the new theory is why no symptoms
of schizophrenia appear for two decades or more if the brain abnormalities
are present from birth.

One answer is that there are, indeed, signs of coming trouble throughout
life but that they are subtle and easily missed. The British Medical
Research Council tracked every child born in Britain in the first week
of
March 1946, assessing them every two years or so until they reached the
age of 43. Dr. Robin Murray, a British psychiatrist, found subtle
childhood differences among those who later developed schizophrenia.

At most milestones of neurological development -- analyzed by looking
at
things like when each infant first sat up and teacher ratings of each
child's performance -- the development of the schizophrenic group, on
average, was delayed.

"There were no gross abnormalities, but a lifelong pattern, on average,
of
delayed maturation of their brains," said Dr. Weinberger, who reviewed
the cumulative evidence linking lifelong neurological problems to
schizophrenia in The Lancet, a medical journal, last year. "For instance,
at six months, about a third of babies are two weeks or more late in
sitting up. For those who later developed schizophrenia, two-thirds were
late. As a whole, their lags suggest subtle abnormalities in neural
development."

When researchers in a 1994 study asked the families of patients with
schizophrenia to provide them with home movies of the patients as
children, they found more signs of unusual neural development. At age
2,
for instance, these children tended to display slightly odd hand movements
that would not have troubled their parents at the time but would have
been
recognized by a trained eye as a sign of troubled motor development.

One of the first bits of evidence came in 1988 from a study of children
born to women who had been pregnant during a severe flu epidemic in
Helsinki, Finland, in 1957. Dr. Sarnoff Mednick, a psychologist at the
University of California at Los Angeles, found that the children of
mothers who had caught flu in the second trimester of pregnancy, the time
when the neural subplate goes into action, had a greater chance of
developing schizophrenia as adults.

Several studies since then have shown that there tends to be a higher
rate
of schizophrenia among children born roughly in the months of December
through March. "If you look at a large enough population -- about
20,000
or more -- you find that there's about a 5 to 6 percent excess of cases
of
schizophrenia born in winter or early spring," said Dr. E. Fuller
Torrey,
a psychiatrist at St. Elizabeth's Hospital in Washington.

In other research, a higher rate of schizophrenia was found among children
in the Netherlands born to women who were pregnant in the winter of
1944-45, when the Nazis blockaded Dutch cities, which suggests that stress and
malnutrition also play a role.

No one cause seems to explain all cases of schizophrenia, which is also,
to some extent, a genetic disorder.

"A whole range of maternal problems during pregnancy that affect
neural
development may increase the risk of a child getting schizophrenia,"
said
Dr. Jed Wyatt, who heads the Neuropsychiatry Branch at the National
Institute of Mental Health. "The hope is that this line of research
could
lead to a preventive strategy one day."

Dr. Torrey agreed, saying, "If some cases are due, for example, to
the
mother's exposure to a virus that passes through the placenta, then
perhaps one day we can identify those viruses and vaccinate women for
it."

He added, "Pregnant women should be reassured that in the vast majority
of
cases where these complications of pregnancy occur, the babies turn out
with no problems at all."

More information on the prenatal factors that have been identified in schizophrenia and mental illness: